PROJECT SUMMARY Asthma is a chronic respiratory disease characterized by reversible airways obstruction and nonspecific airways hyperresponsiveness to inhaled bronchoconstrictors. The ability of anticholinergics to approximate the bronchodilatation achieved by direct acting smooth muscle relaxants and to reduce airways reactivity implicates airway parasympathetic cholinergic nerves as key regulators of asthma pathophysiology. The muscarinic receptor antagonists such as ipratropium and tiotropium are poorly tolerated upon systemic administration and thus require topical application to the airways by aerosol. Limiting the effectiveness of this mode of delivery is the fact that the drugs will work only in those airways accessible to topically-applied therapeutics. Mucus plugging, turbulent, limited and/ or uneven airflow distribution limits drug aerosol access to the distal airways. Anticholinergics also provide little or no relief from chronic cough or dyspnea, symptoms of obstructive lung diseases that contribute adversely to patient quality of life. We hypothesize that a therapeutic strategy that could selectively and reversibly targets as needed all afferent and efferent nerve conduction to and from the airways will provide superior control of asthma symptoms when compared to currently used anticholinergic agents and direct acting bronchodilators. We have been developing peripheral neuromodulation approaches for the treatment of obstructive lung diseases. The vagal neuromodulation techniques achieve peak reversal of baseline cholinergic tone that approximates the effects of topically applied anticholinergics, but with maximal effects attained in only a fraction of the time required by the muscarinic receptor antagonists, can target all nerves projecting to the intrapulmonary airways without the constraints of topical delivery, (e.g. superior to anticholinergics in modulating peripheral airway caliber), can be delivered repeatedly as needed, and if combined with a smart technology, such neuromodulators could provide chronic symptom control in patients with obstructive lung diseases. We will use Synapse device by Nuviant, an FDA approved electrode interface used in patients with chronic pain, to generate preclinical proof of concept data in a well-characterized canine model of obstructive lung diseases. We will incorporate high resolution computed tomography (HRCT), a technique optimized for lung studies in our laboratories, to systematically evaluate and compare the actions of anticholinergics to our neuromodulation approaches on the peripheral airways in vivo. We will evaluate two approaches that can induce a inhibition and/or withdrawal of cholinergic tone in the airways and thus bronchodilatation: the blockade of action potential conduction in the preganglionic parasympathetic nerves innervating the airways, and the selective activation of the large myelinated axons of slowly adapting stretch receptors. We will characterize the performance of Synapse over a range of stimulation frequencies and intensities for their ability to induce dilation of the airways and to reduce or eliminate airways hyper- responsiveness when placed unilaterally or bilaterally on the vagus nerves in acute and subchronic studies.